Heterocyclic compound and antitumor agent containing the same as active ingredient

ABSTRACT

The present invention relates to heterocyclic compounds represented by the formula I or pharmaceutically acceptable salts thereof and antitumor agents containing the heterocyclic compounds as effective components:  
                 
 
     wherein X represents nitrogen atom or CH; R 1  represents CH n F 3-n  (wherein n is 1 or 2), hydroxy C 1 -C 6  alkyl, NHR 6  [wherein R 6  represents hydrogen atom or COR (wherein R represents hydrogen atom, C 1 -C 6  alkyl or C 1 -C 6  alkoxy)]; R 2  represents morpholino (which may be substituted with one to four C 1 -C 6  alkyl), thiomorpholino, piperidino, pyrrolidinyl (which may be substituted with hydroxy C 1 -C 6  alkyl), oxazolidinyl (which may be substituted with one or two C 1 -C 6  alkyl) or tetrahydro-1,4-thiazin- 1 -oxo-4-yl; R 3  and R 4  each represent hydrogen atom or C 1 -C 6  alkyl; and R 5  represents hydrogen atom, amino or hydroxyl.

TECHNICAL FIELD

[0001] The present invention relates to heterocyclic compoundsrepresented by the formula I or pharmaceutically acceptable saltsthereof and antitumor agents containing the heterocyclic compounds aseffective components:

[0002] wherein X represents nitrogen atom or CH; R₁ representsCH_(n)F_(3-n) (wherein n is 1 or 2), hydroxy C₁-C₆ alkyl, NHR₆ [whereinR₆ represents hydrogen atom or COR (wherein R represents hydrogen atom,C₁-C₆ alkyl or C₁-C₆ alkoxy)]; R₂ represents morpholino (which may besubstituted with one to four C₁-C₆ alkyl), thiomorpholino, piperidino,pyrrolidinyl (which may be substituted with hydroxy C₁-C₆ alkyl),oxazolidinyl (which may be substituted with one or two C₁-C₆ alkyl) ortetrahydro-1,4-thiazin-1-oxo-4-yl; R₃ and R₄ each represent hydrogenatom or C₁-C₆ alkyl; and R₅ represents hydrogen atom, amino or hydroxyl.

BACKGROUND ART

[0003] s-Triazine (1,3,5-triazine) and pyrimidine derivatives have beenresearched in the fields of synthetic resins, synthetic fibers, dyes andagricultural chemicals and a number of such compounds have beensynthesized. In the field of pharmaceuticals, researches have been madewith respect to antitumor, anti-inflammatory, analgesic andantispasmodic activities. Especially, hexamethylmelamine (HMM) iswell-known which has been developed as analogue of antitumor agenttriethylenemelamine (TEM) [B. L. Johnson et al. Cancer, 42: 2157-2161(1978)].

[0004] TEM is known as alkylating agent and is an s-triazine derivativehaving cytotoxic antitumor activity. HMM has been marketed in Europeunder the indications for the treatment of ovarian and small cell lungcancers, and its action on solid cancers have attractive.

[0005] Among the s-triazine derivatives, imidazolyl-s-triazinederivatives which exhibit cytotoxic and selective aromatase inhibitoryactivities have been proposed as medicine for estrogen-dependentdiseases such as endometriosis, multicystic ovarium, mastosis,endometrium carcinoma and breast cancer (PCT international publicationWO93/17009).

[0006] However, there is still room for improvement on HMM with respectto its antitumor spectrum and intensity of antitumor activities againstsolid cancers. As to imidazolyl-s-triazine derivatives, they arelimitative in application since they exhibit considerably higheraromatase inhibitory activities than their cytotoxic activities andapplication of them to cancerous patients other than those who sufferfrom estrogen-dependent diseases may lead to development of secondaryeffects such as menstrual disorders due to lack of estrogen. There arestill, therefore, strong demands on medicines with no aromataseinhibitory activities and effective for solid cancers.

DISCLOSURE OF THE INVENTION

[0007] Under such situations and in order to expand antitumor activitiesof HMM and to decrease aromatase inhibitory activities ofimidazolyl-s-triazine derivatives, we, the inventors, carried outintensive studies to find out s-triazine and pyrimidine derivatives withsubstitution of benzimidazole (PCT international publications WO99/05138and WO00/43385).

[0008] However, since even these compounds have not contented anti-tumoractivities, we further developed the studies to find out thatheterocyclic compounds with specific substituents at position 2 ofbenzimidazole ring and represented by the formula I exhibit by farimproved antitumor activities, thus completing the present invention.

[0009] The terms used for definition of letters in the formula I, bywhich the heterocyclic compounds of the present invention arerepresented, will be defined and exemplified in the following.

[0010] The term “C₁-C₆” refers to a group having 1 to 6 carbon atomsunless otherwise indicated.

[0011] The “C₁-C₆ alkyl” refers to a straight- or branched-chain alkylgroup such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl,n-pentyl or n-hexyl.

[0012] The “hydroxy C₁-C₆ alkyl” refers to the above-mentioned “C₁-C₆alkyl” with any of the carbon atoms coupled to hydroxy group.

[0013] The “C₁-C₆ alkoxy” refers to a straight- or branched-chain alkoxygroup such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,tert-butoxy, n-pentyloxy or n-hexyloxy.

[0014] The compounds according to the present invention may be asfollows, though the present invention is not limited to these compounds.

[0015]2-(2-difluoromethylbenzimidazol-1-yl)-4-(cis-2,3-dimethylmorpholino)-6-morpholinopyrimidine

[0016] 2-(2-difluoromethylbenzimidazol-1-yl)-4,6-dimorpholino-pyrimidine

[0017]2-(2-difluoromethylbenzimidazol-1-yl)-4-morpholino-6-thiomorpholinopyrimidine

[0018]2-(2-difluoromethylbenzimidazol-1-yl)-4-(trans-2,3-dimethylmorpholino)-6-morpholinopyrimidine

[0019]2-(2-difluoromethylbenzimidazol-1-yl)-4-(2,2-dimethyl-morpholino)-6-morpholinopyrimidine

[0020]2-(2-difluoromethylbenzimidazol-1-yl)-4-(2-methyl-morpholino)-6-morpholinopyrimidine

[0021]2-(2-difluoromethylbenzimidazol-1-yl)-4-morpholino-6-[2,2,5(R)-trimethylmorpholino]pyrimidine

[0022]2-(2-difluoromethylbenzimidazol-1-yl)-4-morpholino-6-[2,2,5(S)-trimethylmorpholino]pyrimidine

[0023]4-(cis-2,3-dimethylmorpholino)-2-(2-fluoromethyl-benzimidazol-1-yl)-6-morpholinopyrimidine

[0024]2-(2-aminobenzimidazol-1-yl)-4-(cis-2,3-dimethyl-morpholino)-6-morpholinopyrimidine

[0025]2-(2-aminobenzimidazol-1-yl)-4-(trans-2,3-dimethyl-morpholino)-6-morpholinopyrimidine

[0026]4-(cis-2,3-dimethylmorpholino)-2-(2-hydroxymethyl-benzimidazol-1-yl)-6-morpholinopyrimidine

[0027]4-(cis-2,3-dimethylmorpholino)-2-(2-hydroxymethyl-benzimidazol-1-yl)-6-piperidinopyrimidine

[0028]4-(cis-2,3-dimethylmorpholino)-2-(2-hydroxymethyl-benzimidazol-1-yl)-6-(2-hydroxymethylpyrrolidin-1-yl)pyrimidine

[0029]2-(6-amino-2-difluoromethylbenzimidazol-1-yl)-4,6-dimorpholinopyrimidine

[0030]2-(6-amino-2-difluoromethylbenzimidazol-1-yl)-4-(cis-2,3-dimethylmorpholino)-6-morpholinopyrimidine

[0031]2-(2-difluoromethyl-5-hydroxybenzimidazol-1-yl)-4,6-dimorpholinopyrimidine

[0032]2-(2-difluoromethyl-4-hydroxybenzimidazol-1-yl)-4-(2,2-dimethylmorpholino)-6-morpholinopyrimidine

[0033]2-(2,4-diaminobenzimidazol-1-yl)-4-(2,2-dimethyl-morpholino)-6-morpholinopyrimidine

[0034] 2-(2,4-diaminobenzimidazol-1-yl)-4,6-dimorpholino-pyrimidine

[0035]2-(2-amino-4-hydroxybenzimidazol-1-yl)-4-(2,2-dimethyl-morpholino)-6-morpholinopyrimidine

[0036]2-(2-difluoromethylbenzimidazol-1-yl)-4-(cis-2,3-dimethylmorpholino)-6-morpholino-1,3,5-triazine

[0037]2-(2-difluoromethylbenzimidazol-1-yl)-4-(trans-2,3-dimethylmorpholino)-6-morpholino-1,3,5-triazine

[0038]2-(2-difluoromethylbenzimidazol-1-yl)-4-(2,2-dimethylmorpholino)-6-morpholino-1,3,5-triazine

[0039]2-(2-difluoromethylbenzimidazol-1-yl)-4-morpholino-6-thiomorpholino-1,3,5-triazine

[0040]2-(2-difluoromethylbenzimidazol-1-yl)-4-(2-methyl-morpholino)-6-morpholino-1,3,5-triazine

[0041]2-(2-difluoromethylbenzimidazol-1-yl)-4-(trans-2,5-dimethylmorpholino)-6-morpholino-1,3,5-triazine

[0042]2-(2-difluoromethylbenzimidazol-1-yl)-4,6-dimorpholino-1,3,5-triazine

[0043]2-(2-difluoromethylbenzimidazol-1-yl)-4-morpholino-6-[2,2,5(R)-trimethylmorpholino]-1,3,5-triazine

[0044]2-(2-difluoromethylbenzimidazol-1-yl)-4-morpholino-6-(tetrahydro-1,4-thiazin-1-oxo-4-yl)-1,3,5-triazine

[0045]2-(2-acetylaminobenzimidazol-1-yl)-4,6-dimorpholino-1,3,5-triazine

[0046]2-(2-acetylaminobenzimidazol-1-yl)-4-(trans-2,3-dimethylmorpholino)-6-morpholinopyrimidine

[0047]2-(2-formylaminobenzimidazol-1-yl)-4,6-dimorpholino-1,3,5-triazine

[0048]2-(2-propionylaminobenzimidazol-1-yl)-4-(trans-2,3-dimethylmorpholino)-6-morpholino-1,3,5-triazine

[0049]2-(trans-2,3-dimethylmorpholino)-4-(2-formylamino-benzimidazol-1-yl)-6-morpholino-1,3,5-triazine

[0050]4-(trans-2,3-dimethylmorpholino)-2-(2-formylamino-benzimidazol-1-yl)-6-morpholinopyrimidine

[0051]2-(cis-2,6-dimethylmorpholino)-4-(2-formylamino-benzimidazol-1-yl)-6-morpholino-1,3,5-triazine

[0052]2-(2-methoxycarbonylaminobenzimidazol-1-yl)-4,6-dimorpholino-1,3,5-triazine

[0053] 2-(2-aminobenzimidazol-1-yl)-4,6-dimorpholino-1,3,5-triazine

[0054]2-(2-aminobenzimidazol-1-yl)-4-(trans-2,3-dimethyl-morpholino)-6-morpholino-1,3,5-triazine

[0055]2-(2-aminobenzimidazol-1-yl)-4-(cis-2,3-dimethyl-morpholino)-6-piperidino-1,3,5-triazine

[0056]2-(2-difluoromethylbenzimidazol-1-yl)-4-morpholino-6-piperidino-1,3,5-triazine

[0057]2-(2-difluoromethylbenzimidazol-1-yl)-4-(trans-2,3-dimethylmorpholino)-6-(2-hydroxymethylpyrrolidin-1-yl)-1,3,5-triazine

[0058]2-(6-amino-2-difluoromethylbenzimidazol-1-yl)-4-(2,2-dimethylmorpholino)-6-morpholino-1,3,5-triazine

[0059]2-(6-amino-2-difluoromethylbenzimidazol-1-yl)-4-(cis-2,3-dimethylmorpholino)-6-morpholino-1,3,5-triazine

[0060]2-(4-amino-2-difluoromethylbenzimidazol-1-yl)-4,6-dimorpholino-1,3,5-triazine

[0061]2-(2-difluoromethyl-5-hydroxybenzimidazol-1-yl)-4-(2,3-cis-dimethylmorpholino)-6-morpholino-1,3,5-triazine

[0062]2-(2-difluoromethyl-6-hydroxybenzimidazol-1-yl)-4-(2,2-dimethylmorpholino)-6-morpholino-1,3,5-triazine

[0063]2-(2-difluoromethyl-5-hydroxybenzimidazol-1-yl)-4-(2,2-dimethyloxazolidin-3-yl)-6-morpholino-1,3,5-triazine

[0064]2-(2-difluoromethyl-4-hydroxybenzimidazol-1-yl)-4,6-dimorpholino-1,3,5-triazine

[0065]2-(2-difluoromethyl-4-hydroxybenzimidazol-1-yl)-4-(2,2-dimethylmorpholino)-6-morpholino-1,3,5-triazine

[0066]2-(2,4-diaminobenzimidazol-1-yl)-4-(2,2-dimethyl-morpholino)-6-morpholino-1,3,5-triazine

[0067] 2-(2,4-diaminobenzimidazol-1-yl)-4,6-dimorpholino-1,3,5-triazine

[0068]2-(2-amino-4-hydroxybenzimidazol-1-yl)-4-(2,2-dimethyl-morpholino)-6-morpholino-1,3,5-triazine

[0069] The compounds of the present invention may have asymmetric carbonatoms in the structure. It is to be understood that isomers due to suchasymmetric carbon atom or combination (racemate) of any of the isomersare included in the category of the compounds according to the presentinvention.

[0070] Furthermore, the compounds of the present invention may be in theform of pharmaceutically acceptable acid addition salts. The appropriateacid addition salts which can be used include, for example, inorganicsalts such as hydrochloride, sulfate, hydrobromide, nitrate andphosphate as well as organic acid salts such as acetate, oxalate,propionate, glycolate, lactate, pyruvate, malonate, succinate, maleate,fumarate, malate, tartarate, citrate, benzoate, cinnamate,methanesulfonate, benzenesulfonate, p-toluenesulfonate and salicylate.

[0071] Production Processes

[0072] The compounds of the present invention represented by the formulaI may be prepared by, as shown in the following reaction formula,reacting cyanuric chloride or 2,4,6-trichloropyrimidine (Compound II) asstarting material with benzimidazole compound (Compound V), morpholinecompound (Compound VI) and R₂H (Compound VII) successively in the ordernamed.

[0073] wherein R₁, R₂, R₃, R₄, R₅ and X are as defined above and R′represents hydrogen atom, nitro or tertbutyldimethyl-silyloxy.

[0074] Next, the respective production processes will be described.

[0075] 1) Production Process (i) of Intermediate III:

[0076] wherein R₁, R′ and X are as defined above.

[0077] In a solvent, cyanuric chloride or 2,4,6-trichloropyrimidine(Compound II) is reacted with benzimidazole compound (Compound V) in thepresence of hydrogen chloride trapping agent to obtain the intermediateIII.

[0078] The hydrogen chloride trapping agent used in this reaction maybe, for example, sodium hydroxide, potassium hydroxide, sodiumcarbonate, potassium carbonate, triethylamine or pyridine. The solventused may be acetone, toluene, hexane, xylene, dioxane, tetrahydrofuranor dichloroethane or N,N-dimethylformamide (DMF).

[0079] In this reaction, 0.5-1.2 moles of the compound V is used permole of the compound II in the presence of 0.5-1.2 moles of the hydrogenchloride trapping agent. The reaction is made at the temperature of −15°C.—5° C. for 0.5-2 hours, and further at the room temperature for 5-50hours.

[0080] It is to be noted that the compound V may be also used as thehydrogen chloride trapping agent.

[0081] 2) Production Process (ii) of Intermediate IV

[0082] wherein R₁, R₃, R₄, R′ and X are as defined above.

[0083] In the solvent, the intermediate III obtained in theabove-mentioned production process (i) is reacted with morpholinecompound (Compound VI) in the presence of hydrogen chloride trappingagent to obtain the intermediate IV. The hydrogen chloride trappingagent used in this reaction may be the same as those in theabove-mentioned production process (i). The solvent used may be DMF,acetone, toluene, xylene, dichloroethane or dichloromethane.

[0084] In this reaction, 0.5-1.2 moles of the compound VI is used permole of the intermediate III and in the presence of 0.5-3 moles of thehydrogen chloride trapping agent. The reaction is made at thetemperature of −5° C.-0° C. for 0.5-3 hours, and further at the roomtemperature for 5-50 hours.

[0085] It is to be noted that the compound VI may be also used as thehydrogen chloride trapping agent.

[0086] 3) Production Process (iii) of the compound 1

[0087] wherein R₁, R₂, R₃, R₄, R₅, R′ and X are as defined above.

[0088] In the solvent, the intermediate IV obtained in theabove-mentioned production process (ii) is reacted with R₂H (CompoundVII) in the presence of hydrogen chloride trapping agent to obtain thecompound 1 according to the present invention.

[0089] The hydrogen chloride trapping agent used in this reaction may bethe same as those in the above-mentioned production process (i). Thesolvent used may be DMF, dimethyl sulfoxide (DMSO), xylene ordichloroethane.

[0090] In this reaction, 1-5 moles of R₂H (the compound VII) is used permole of the intermediate IV at the temperature between room temperatureand 140° C. for 0.1-16 hours. In the case of the reaction in thepresence of the hydrogen chloride trapping agent, 1-5 moles of thehydrogen chloride trapping agent is used per mole of the intermediateIV. It is to be noted that the compound VII may be also used as thehydrogen chloride trapping agent.

[0091] In such production of the compound 1 and when the compounds VIand VII are the same, the production processes (ii) and (iii) may becarried out in a single step to obtain the compound I. In this case, thereaction conditions are as mentioned in the above with respect to theproduction process (ii) except that 2-10 moles of the compound VI or VIIis used per mole of the compound III and that the reaction is made atthe temperature of −10° C.-5° C. for 0.1-5 hours, and further at thetemperature between room temperature and 120° C. for 3-50 hours.

[0092] When the compound V, VI or VII used in the production process(i), (ii) or (iii) has lower reactivity, it is preferable that theproduction process is carried out after treatment with sodium hydride.In the case of sodium hydride being used, 1.0-1.2 moles of sodiumhydride is used per mole of the starting material in the productionprocess (Compound II, III or IV).

[0093] When R₁ has hydroxyl or when R₅ is hydroxyl, the reaction iscarried out, using benzimidazole compound with hydroxylprotected byalkylsilyl group such as tert-butyldimethylsilyl according to ordinarymethod; in a final step, the protective group is removed to obtain theaimed compound. When R₅ is amino, the reaction is carried out, usingbenzimidazole with substitution of nitro; in a final step, catalyticreduction is carried out by ordinary method under a hydrogen atmosphereto obtain the aimed compound.

[0094] The above-mentioned production processes (i), (ii) and (iii) maybe carried out in any exchanged order. In such a case, the reactionconditions may be varied to an extent obvious to ordinary experts in theart.

[0095] The resultant products in the above-mentioned respectiveproduction processes may be separated and purified, as needs demand, byordinary method such as extraction, condensation, neutralization,filtration, re-crystallization or column chromatography.

[0096] Acid-addition salts of the compounds 1 of the present inventionmay be prepared according to various methods well-known in the art. Theappropriate acids used include, for example, inorganic acids such ashydrochloric, sulfuric, hydrobromic, nitric or phosphoric acid, andorganic acids such as acetic, oxalic, propionic, glycolic, lactic,pyruvic, malonic, succinic, maleic, fumaric, malic, tartaric, citric,benzoic, cinnamic, methanesulfonic, benzenesulfonic, p-toluenesulfonicor salicylic acid.

[0097] Next, antitumor activities of the compounds 1 of the presentinvention will be described. Numbers of the tested compounds in thetests 1 and 2 correspond to those in Examples referred to hereinafter.

[0098] Comparative compounds used were the following s-triazine-seriesantitumor agents or medicines for estrogen-dependent diseases:

[0099] Compound A:2-(benzimidazol-1-yl)-4-(trans-2,3-dimethylmorpholino)-6-morpholinopyrimidine(a typical compound disclosed in the international publicationWO99/05138)

[0100] Compound B:2-(2-methylbenzimidazol-1-yl)-4,6-dimorpholino-1,3,5-triazine (a typicalcompound disclosed in the international publication WO99/05138)

[0101] Compound C: 2-(imidazol-1-yl)-4,6-dimorpholino-1,3,5-triazine(typical compound disclosed in the international publication WO93/17009)

[0102] Compound D: hexamethylmelamine (HMM)

[0103] Test 1

[0104] Used in the test were MCF-7 cells which were established fromhuman breast cancer and were cultured routinely under the conditions of37° C. and 5% CO₂, in MEM medium supplemented with 10% fetal calf serum,25 mM of HEPES and 0.1 mg/ml of kanamycin. The MCF-7 cells in alogarithmic growth phase were treated with trypsin/EDTA to preparesingle cell suspension adjusted to 4.0×10⁴ cells/ml in MEM medium(supplemented with 10% fetal calf serum, 25 mM of HEPES and 0.1 mg/ml ofkanamycin). Test compounds were dissolved in DMSO and diluted with RPMI1640 medium (supplemented with 10% fetal calf serum, 25 mM of HEPES and0.1 mg/ml of kanamycin) to a concentration of 2.0×10⁻⁴-2.0×10⁻⁹ M.

[0105] The cell suspension was filled in a 96-wells microplate at a rateof 0.1 ml per well and was cultured for 24 hours so as to make the cellsadhered to the microplate. Then, it was added with 0.1 ml of the samplesolution and cultured at 37° C. for 72 hours in 5% CO₂. 50% Growthinhibition concentrations (GI₅₀ 9M) were calculated from growthinhibitions at various sample concentrations. The results are as shownin Table 1. TABLE 1 test compound GI₅₀ (μM) test compound GI₅₀ (μM)compound 1 0.11 compound 23 0.19 compound 2 0.21 compound 25 0.19compound 3 0.38 compound 26 <0.04 compound 4 0.18 compound 27 0.16compound 5 0.22 compound 29 0.25 compound 6 0.29 compound 30 0.25compound 8 0.32 compound 31 0.24 compound 9 0.20 compound 32 0.18compound 10 0.13 compound 33 0.08 compound 11 0.20 compound 34 0.08compound 12 0.39 compound 35 0.14 compound 14 0.16 compound 36 0.29compound 15 0.13 compound 37 0.09 compound 16 0.35 compound 38 0.03compound 17 0.12 compound 39 0.06 compound 18 0.18 compound 40 0.21compound 19 0.09 compound A 2.2 compound 20 0.22 compound B 3.7 compound21 0.34 compound C 20 compound 22 0.23 compound D >100

[0106] The above test results clearly revealed that the compounds of thepresent invention exhibit by far superior antitumor activities on humanbreast cancer cells than the known comparative compounds A, B, C and D.

[0107] The compounds of the present invention were also effective invitro tests using human non small cell lung cancer cells and humancolonic cancer cells and therefore positively expected is application ofthe compounds according to the present invention on treatment of varioushuman solid cancers.

[0108] Test 2

[0109] Human colon cancer WiDr was grown as subcutaneous tumor in mutantBALA/c nude mice. 2-mm-cube tumor fragments were transplantedsubcutaneously into left flank of the nude mice. When the tumor reachedlogarithmic growth phase, mice were divided randomly into test groupsconsisting five mice per group. The samples prepared by dissolving testcompounds in physiological saline solution or suspending them in 1%hydroxypropyl cellulose (HPC), using an agate mortar, wereintraperitoneally administered at a rate of 200 mg/kg, once a day andsix times a week in total, for two weeks. Major and minor axes of thetumor mass were measured on a daily basis to calculate tumor volume. Thetumor volume at each measured day was divided by that at the start dayof the sample administration to calculate relative tumor growth rate;and the relative tumor growth rate of the treated groups (T) and that ofthe control group (C) were used to calculate T/C (%). Cases where T/C(%) of the last day was less than 50% and U-assay of Mann-Whitneyrevealed significant difference with one-sided risk rate of 1% werejudged to be effective (+). The results are as shown in Table 2. TABLE 2test compound judgment compound 14 + compound 19 + compound 22 +compound 31 + compound 32 + compound 33 + compound A −

[0110] Next, description will be made on ways of administration,appearances and administered amount of the compounds of the presentinvention where they are applied to mammals, especially to human.

[0111] The compounds of the present invention may be administered orallyor parenterally. In oral administration, the compounds may be in theappearance of tablets, coated tablets, powders, granules, capsules,microcapsules, syrups and the like; and in parenteral administration, inthe appearance of injections which may include soluble freeze-dryingappearance, suppositories and the like. In the preparation of theseappearances, pharmaceutically acceptable excipient, binders, lubricants,disintegrators, suspensions, emulsifiers, antiseptics, stabilizers anddispersing agents, for example, lactose, sucrose, starch, dextrin,crystalline cellulose, kaolin, calcium carbonate, talc, magnesiumstearate, distilled water and physiological saline solution may be used.

[0112] The dosage for humans may depend on the condition of the diseaseto be treated, the age and weight of the patient and the like. A dailydosage for an adult may be in the range of from 100 to 1,000 mg and maybe given in divided doses 2 or 3 times a day.

BEST MODE FOR CARRYING OUT THE INVENTION

[0113] Next, the present invention is more specifically illustrated withreference to the following Examples of the compounds. It is to be,however, noted that the present invention is not limited to theseExamples.

EXAMPLE 1

[0114]2-(2-difluoromethylbenzimidazol-1-yl)-4-(cis-2,3-dimethylmorpholino)-6-morpholinopyrimidine(Compound 1)

[0115] (1) 0.84 g (5 mmol) of 2-difluoromethylbenzimidazole dissolved inDMF (25 ml) was added and reacted with 60% sodium hydride (0.24 g, 6mmol) at room temperature for 30 minutes. This suspension was added to asolution of 2,4,6-trichloropyrimidine (0.92 g, 5 mmol) dissolved in DMF(25 ml) and stirred at room temperature for 1.5 hours. The reactionsolution was poured into water and the resulting precipitates wererecrystallized from methanol to obtain 0.98 g (yield: 62%) of4,6-dichloro-2-(2-difluoromethylbenzimidazol-1-yl)pyrimidine.

[0116] (2) 0.32 g (1.0 mmol) of4,6-dichloro-2-(2-difluoro-methylbenzimidazol-1-yl)pyrimidine, 0.16 g(1.0 mmol) of cis-2,3-dimethylmorpholine hydrochloride and 0.3 g (2.2mmol) of anhydrous potassium carbonate were added to DMF (10 ml) andstirred at room temperature for 16 hours. The reaction solution waspoured into water and extracted with ethyl acetate. The separatedorganic layer was washed with water and dried over anhydrous magnesiumsulfate. The solvent was removed under reduced pressure and the residuewas purified by silica gel column chromatography to obtain 0.33 g(yield: 84%) of4-chloro-2-(2-difluoro-methylbenzimidazol-1-yl)-6-(cis-2,3-dimethylmorpholino)-pyrimidine.

[0117] (3) 0.33 g (0.8 mmol) of the obtained4-chloro-2-(2-difluoromethylbenzimidazol-1-yl)-6-(cis-2,3-dimethyl-morpholino)pyrimidinedissolved in morpholine (0.70 g, 8.0 mmol) was stirred at 70° C. for 1hour. The solvent was removed under the reduced pressure from thereaction mixture and the residue was purified by silica gel columnchromatography to obtain 0.326 g (yield: 90%) of the titled compound ascolorless crystals.

[0118] Melting point: 167-169° C.

[0119] NMR(CDCl₃): 1.37(3H, d, J=7 Hz), 1.38(3H, d, J=7 Hz),3.3-4.2(14H, m), 5.47(1H, s), 7.3-7.5(2H, m), 7.51(1H, t, J=53 Hz),7.8-8.0(1H, m), 8.2-8.3(1H, m)

[0120] MS m/z: 444(M⁺)

[0121] In accordance with the procedure of the Example 1, the followingcompounds were prepared from the corresponding starting materials.

[0122] 2-(2-difluoromethylbenzimidazol-1-yl)-4,6-dimorpholino-pyrimidine(Compound 2)

[0123] Melting point: 201-202° C.

[0124] NMR (CDCl₃) δ: 3.63(8H, t, J=5 Hz), 3.83(8H, t, J=5 Hz), 5.51(1H,s), 7.3-7.4(2H, m), 7.51(1H, t, J=53 Hz), 7.8-7.9(1H, m), 8.2-8.3(1H, m)

[0125] MS m/z: 416(M⁺)

[0126]2-(2-difluoromethylbenzimidazol-1-yl)-4-morpholino-6-thiomorpholinopyrimidine(Compound 3)

[0127] Melting point: 173-175° C.

[0128] NMR(CDCl₃) δ:2.71(4H, t, J=5 Hz), 3.63(4H, t, J=5 Hz), 3.83(4H,t, J=5 Hz), 4.03(4H, t, J=5 Hz), 5.49(1H, s), 7.3-7.4(2H, m), 7.50(1H,t, J=53 Hz), 7.8-7.9(1H, m), 8.3-8.4(1H, m)

[0129] MS m/z:432(M⁺)

[0130]2-(2-difluoromethylbenzimidazol-1-yl)-4-(trans-2,3-dimethylmorpholino)-6-morpholinopyrimidine(Compound 4)

[0131] Melting point: 172-174° C.

[0132] NMR(CDCl₃) δ: 1.22(3H, d, J=7 Hz), 1.23(3H, d, J=7 Hz),3.2-4.1(14H, m), 5.47(1H, s), 7.3-7.5(2H, m), 7.51(1H, t, J=53 Hz),7.8-8.0(1H, m), 8.2-8.3(1H, m)

[0133] MS m/z: 444(M⁺)

[0134]2-(2-difluoromethylbenzimidazol-1-yl)-4-(2,2-dimethyl-morpholino)-6-morpholinopyrimidine(Compound 5)

[0135] Melting point: 149-152° C.

[0136] NMR(CDCl₃) δ: 1.30(6H, s), 3.50(2H, s), 3.5-3.9(12H, m), 5.48(1H,s), 7.3-7.5(2H, m), 7.50(1H, t, J=53 Hz), 7.8-8.0(1H, m), 8.2-8.3(1H, m)

[0137] MS m/z: 444(M⁺)

[0138]2-(2-difluoromethylbenzimidazol-1-yl)-4-(2-methyl-morpholino)-6-morpholinopyrimidine(Compound 6)

[0139] Melting point: 126-131° C.

[0140] NMR(CDCl₃) δ: 1.29(3H, d, J=6 Hz), 2.7-2.9(1H, m), 3.0-3.2(1H,m), 3.6-4.2(13H, m), 5.51(1H, s), 7.3-7.5(2H, m), 7.51(1H, t, J=53 Hz),7.8-8.0(1H, m), 8.2-8.3(1H, m)

[0141] MS m/z: 430(M⁺)

[0142]2-(2-difluoromethylbenzimidazol-1-yl)-4-morpholino-6[2,2,5(R)-trimethylmorpholino]pyrimidine(Compound 7)

[0143] Melting point: 113-116° C.

[0144] NMR(CDCl₃) δ: 1.2-1.4(9H, m), 3.0-3.1(1H, d, J=13 Hz),3.5-4.1(11H, m), 4.2-4.4(1H, m), 5.46(1H, s), 7.3-7.5(1H, s), 7.51(1H,t, J=53 Hz), 7.8-8.0(1H, m), 8.2-8.3(1H, m)

[0145] MS m/z: 458(M⁺)

[0146]2-(2-difluoromethylbenzimidazol-1-yl)-4-morpholino-6-[2,2,5(S)-trimethylmorpholino]pyrimidine(Compound 8)

[0147] Melting point: 113-116° C.

[0148] NMR(CDCl₃) δ: 1.2-1.4(9H, m), 3.0-3.1(1H, d, J=13 Hz),3.5-4.1(11H, m), 4.2-4.4(1H, m), 5.46(1H, s), 7.3-7.5(1H, s), 7.51(1H,t, J=53 Hz), 7.8-8.0(1H, m), 8.2-8.3(1H, m)

[0149] MS m/z: 458(M⁺)4-(cis-2,3-dimethylmorpholino)-2-(2-fluoromethyl-benzimidazol-1-yl)-6-morpholinopyrimidine(Compound 9)

[0150] Melting point: 163-165° C.

[0151] NMR(CDCl₃) δ: 1.36(3H, d, J=5 Hz), 1.39(3H, d, J=5 Hz),3.3-3.5(1H, m), 3.6-4.2(13H, m), 5.46(1H, s), 5.97(2H, d, J=47 Hz),7.3-7.4(2H, m), 7.8-7.9(1H, m), 8.2-8.3(1H, m)

[0152] MS m/z: 426(M⁺)

EXAMPLE 2

[0153]2-(2-aminobenzimidazol-1-yl)-4-(cis-2,3-dimethyl-morpholino)-6-morpholinopyrimidine

[0154] In accordance with the procedure of the Example 1 except that2-difluoromethylbenzimidazole in (1) of the Example 1 was replaced by2-aminobenzimidazole, 27 mg (yield: 90%) of the titled compound wasobtained as colorless crystals.

[0155] Melting point: 129-133° C.

[0156] NMR(CDCl₃) δ: 1.20(3H, d, J=7 Hz), 1.23(3H, d, J=7 Hz),3.2-4.2(14H, m), 5.43(1H, s), 6.62(2H, brs), 7.0-7.4(3H, m), 8.1-8.2(1H,m)

[0157] MS m/z: 409(M⁺)

[0158] In accordance with the procedure of the Example 2, the followingcompound was prepared from the corresponding starting material.

[0159]2-(2-aminobenzimidazol-1-yl)-4-(trans-2,3-dimethyl-morpholino)-6-morpholinopyrimidine

[0160] Melting point: 118-123° C.

[0161] NMR(CDCl₃) δ: 1.36(3H, d, J=7 Hz), 1.39(3H, d, J=7 Hz),3.3-4.2(14H, m), 5.42(1H, s), 6.63(2H, brs), 7.0-7.4(3H, m), 8.1-8.2(1H,m)

[0162] MS m/z: 409(M⁺)

EXAMPLE 3

[0163]4-(cis-2,3-dimethylmorpholino)-2-(2-hydroxymethyl-benzimidazol-1-yl)-6-morpholinopyrimidine(Compound 10)

[0164] In accordance with the procedure of the Example 1 except that2-difluoromethylbenzimidazole in (1) of the Example 1 was replaced by2-tert-butyldimethylsilyloxy-methyl-benzimidazole, 1.62 g (yield: 80%)of2-(2-tert-butyldimethylsilyloxymethylbenzimidazol-1-yl)-4-(cis-2,3-dimethylmorpholino)-6-morpholinopyrimidinewas obtained. 1.62 g (3.0 mmol) of the obtained compound dissolved inTHF (10 ml) was added with tetrabutylammoniumfluoride (1.18 g, 4.5 mmol)and stirred at room temperature for 30 minutes. The reaction solutionwas poured into water and dealt with in accordance with the procedure of(2) of the Example 1 and purified by column chromatography to obtain0.86 g (yield: 67%) of the titled compound as colorless crystals.

[0165] Melting point: 125-128° C.

[0166] NMR(CDCl₃) δ: 1.37 (3H, t, J=7 Hz), 1.39 (3H, d, J=7 Hz),3.3-4.2(14H, m), 5.13(2H, s), 5.46(1H, s), 7.2-7.4(2H, m), 7.7-7.8(1H,m), 8.2-8.3(1H, m)

[0167] MS m/z: 424(M⁺)

[0168] In accordance with the procedure of the Example 3, the followingcompounds were prepared from the corresponding starting materials.

[0169]4-(cis-2,3-dimethylmorpholino)-2-(2-hydroxymethyl-benzimidazol-1-yl)-6-piperidinopyrimidine(Compound 11)

[0170] Melting point: 141-143° C.

[0171] NMR(CDCl₃) δ:1.36(3H, t, J=7 Hz), 1.39(3H, d, J=7 Hz), 1.70(6H,m), 3.3-3.5(1H, m), 3.6-4.2(9H, m), 4.76(1H, s), 5.13(2H, s), 5.46(1H,s), 7.2-7.4(2H, m), 7.7-7.8(1H, m), 8.2-8.4(1H, m)

[0172] MS m/z: 422(M⁺)

[0173]4-(cis-2,3-dimethylmorpholino)-2-(2-hydroxymethyl-benzimidazol-1-yl)-6-(2-hydroxymethylpyrrolidin-1-yl)pyrimidine(Compound 12)

[0174] Melting point: 104-108° C.

[0175] NMR(CDCl₃) δ: 1.37(3H, t, J=7 Hz), 1.39(3H, d, J=7 Hz),2.0-2.2(4H, m), 3.3-4.4(10H, m), 4.9-5.2(2H, m), 5.30(1H, d, J=2 Hz),5.4-5.5(1H, m), 7.3-7.4(2H, m), 7.7-7.8(1H, m), 8.2-8.3(1H, m)

[0176] MS m/z: 438(M⁺)

EXAMPLE 4

[0177]2-(2-difluoromethylbenzimidazol-1-yl)-4-(cis-2,3-dimethylmorpholino)-6-morpholino-1,3,5-triazine(Compound 13)

[0178] (1) 11.8 g (50 mmol) of 2,4-dichloro-6-morpholino-1,3,5-triazine,8.41 g (50 mmol) of 2-difluoromethyl-benzimidazole and 55.3 g (400 mmol)of anhydrous potassium carbonate added to DMF (250 ml) were stirred atroom temperature for 16 hours. The reaction solution was poured intowater and the resulting precipitates were washed with DMF and ethanol toobtain 15.7 g (yield: 86%) of4-chloro-2-(2-difluoromethylbenzimidazol-1-yl)-6-morpholino-1,3,5-triazine.

[0179] (2) 0.36 g (0.98 mmol) of the obtained4-chloro-2-(2-difluoromethylbenzimidazol-1-yl)-6-morpholino-1,3,5-triazine,0.16 g (1.0 mmol) of cis-2,3-dimethylmorpholine hydrochloride and 0.3 g(2.2 mmol) of anhydrous potassium carbonate added to DMF (10 ml) werestirred at room temperature for 16 hours. The reaction solution waspoured into water and extracted with ethyl acetate. The separatedorganic layer was washed with water and dried over anhydrous magnesiumsulfate. The solvent was removed under reduced pressure and the residuewas purified by silica gel column chromatography to obtain 0.38 g(yield: 87%) of the titled compound as colorless crystals.

[0180] Melting point: 207-210° C.

[0181] NMR(CDCl₃) δ: 1.34(3H, d, J=7 Hz), 1.41(3H, d, J=7 Hz),3.3-3.5(1H, m), 3.7-4.0(11H, m), 4.4-4.6(2H, m), 7.3-7.5(2H, m),7.57(1H, t, J=53 Hz), 7.8-8.0(1H, m), 8.2-8.3(1H, m)

[0182] MS m/z: 445(M⁺)

[0183] In accordance with the procedure of the Example 4, the followingcompounds were prepared from the corresponding starting materials.

[0184]2-(2-difluoromethylbenzimidazol-1-yl)-4-(trans-2,3-dimethylmorpholino)-6-morpholino-1,3,5-triazine(Compound 14)

[0185] Melting point: 135-138° C.

[0186] NMR(CDCl₃): 1.23(3H, d, J=6 Hz), 1.24(3H, d, J=6 Hz), 3.1-3.4(1H,m), 3.5-4.1(11H, m), 4.3-4.7(2H, m), 7.3-8.0(4H, m), 8.3-8.4(1H, m)

[0187] MS m/z: 445(M⁺)

[0188]2-(2-difluoromethylbenzimidazol-1-yl)-4-(2,2-dimethyl-morpholino)-6-morpholino-1,3,5-triazine(Compound 15)

[0189] Melting point: 176-178° C.

[0190] NMR(CDCl₃) δ: 1.29(6H, s), 3.6-3.9(14H, m), 7.3-8.0(4H, m),8.3-8.4(1H, m)

[0191] MS m/z: 445(M⁺)

[0192]2-(2-difluoromethylbenzimidazol-1-yl)-4-morpholino-6-thiomorpholino-1,3,5-triazine(Compound 16)

[0193] Melting point: 215-217° C.

[0194] NMR(CDCl₃) δ: 2.71(4H, t, J=5 Hz), 3.80(4H, t, J=5 Hz), 3.87(4H,t, J=5 Hz), 4.18(4H, t, J=5 Hz), 7.3-7.5(2H, m), 7.55(1H, t, J=53 Hz),7.8-7.9(1H, m), 8.3-8.4(1H, m)

[0195] MS m/z: 433(M⁺)

[0196]2-(2-difluoromethylbenzimidazol-1-yl)-4-(2-methyl-morpholino)-6-morpholino-1,3,5-triazine(Compound 17)

[0197] Melting point: 188-191° C.

[0198] NMR(CDCl₃) δ: 1.28(3H, d, J=6 Hz), 2.7-2.9(1H, m), 3.0-3.3(1H,m), 3.5-4.1(11H, m), 4.5-4.6(2H, m), 7.3-7.5(2H, m), 7.56(1H, t, J=53Hz), 7.8-8.0(1H, m), 8.2-8.4(1H, m)

[0199] MS m/z: 431(M⁺)

[0200]2-(2-difluoromethylbenzimidazol-1-yl)-4-(trans-2,5-dimethylmorpholino)-6-morpholino-1,3,5-triazine(Compound 18)

[0201] Melting point: 166-169° C.

[0202] NMR(CDCl₃) δ: 1.31(3H, d, J=7 Hz), 1.39(3H, d, J=7 Hz),3.4-4.3(13H, m), 4.6-4.8(1H, m), 7.3-7.5(2H, m), 7.58(1H, t, J=7 Hz),7.8-8.0(1H, m), 8.2-8.3(1H, m)

[0203] MS m/z: 445(M⁺)

[0204]2-(2-difluoromethylbenzimidazol-1-yl)-4,6-dimorpholino-1,3,5-triazine(Compound 19)

[0205] Melting point: 211-214° C.

[0206] NMR(CDCl₃) δ: 3.79(8H, t, J=4 Hz), 3.88(8H, t, J=4 Hz),7.3-7.4(2H, m), 7.56(1H, t, J=53 Hz), 7.88(1H, d, J=7 Hz), 8.32(1H, d,J=7 Hz)

[0207] MS m/z: 417(M⁺)

[0208]2-(2-difluoromethylbenzimidazol-1-yl)-4-morpholino-6-[2,2,5(R)-trimethylmorpholino]-1,3,5-triazine(Compound 20)

[0209] Melting point: 169-171° C.

[0210] NMR(CDCl₃) δ: 1.2-1.4(9H, m), 3.0-3.2(1H, m)), 3.5-4.1(10H, m),4.29(1H, d, J=13 Hz), 4.6-4.8(1H, m), 7.3-7.8(3H, m), 7.8-8.0(1H, m),8.2-8.4(1H, m)

[0211] MS m/z: 459(M⁺)

EXAMPLE 5

[0212]2-(2-difluoromethylbenzimidazol-1-yl)-4-morpholino-6-(tetrahydro-1,4-thiazin-1-oxo-4-yl)-1,3,5-triazine(Compound 21)

[0213] 0.61 g (1.4 mmol) of2-(2-difluoromethylbenzimidazol-1-yl)-4-morpholino-6-thiomorpholino-1,3,5-triazinedissolved in dichloromethane (20 ml) was added with m-chloroperbenzoicacid (0.35 g, 2.0 mmol) and stirred at room temperature for 16 hours.The reaction solution was poured into water and extracted with ethylacetate. The separated organic layer was washed with water and driedover anhydrous magnesium sulfate. The solvent was removed under reducedpressure and the residue was purified by silica gel columnchromatography to obtain 0.27 g (yield: 42%) of the titled compound ascolorless crystals.

[0214] Melting point: 225-226° C.

[0215] NMR(CDCl₃) δ: 2.7-2.9(2H, m), 2.9-3.0(2H, m), 3.7-4.0(8H, m),4.1-4.3(2H, m), 4.6-4.8(2H, m), 7.4-7.5(2H, m), 7.52(1H, t, J=53 Hz),7.8-7.9(1H, m), 8.3-8.4(1H, m)

[0216] MS m/z: 449(M⁺)

EXAMPLE 6

[0217]2-(2-acetylaminobenzimidazol-1-yl)-4,6-dimorpholino-1,3,5-triazine(Compound 22)

[0218] (1) 9.32 g (70 mmol) of 2-aminobenzimidazole dissolved in DMF(300 ml) was added and reacted with 60% sodium hydride (2.80 g, 70 mmol)at room temperature for 30 minutes. This suspension was added to asolution of 14.3 g (50 mmol) of 2-chloro-4,6-dimorpholino-1,3,5-triazinedissolved in DMF (200 ml) and stirred at room temperature for 2 hours.The reaction solution was poured into water and the resultingprecipitates were washed with water and methanol to obtain 17.7 g(yield: 93%) of2-(2-aminobenz-imidazol-1-yl)-4,6-dimorpholino-1,3,5-triazine.

[0219] (2) 0.38 g (1.0 mmol) of2-(2-aminobenzimidazol-1-yl)-4,6-dimorpholino-1,3,5-triazine and 0.24 g(4.0 mmol) of acetic acid were added to and further 0.83 g (4.0 mmol) ofDCC was added to chloroform (5 ml) and stirred at room temperature for 4hours. The reaction solution was poured into water and extracted withethyl acetate. The separated organic layer was washed with water anddried over anhydrous magnesium sulfate. The solvent was removed underreduced pressure and the residue was purified by silica gel columnchromatography to obtain 0.31 g (yield: 73%) of the titled compound ascolorless crystals.

[0220] Melting point: 243-245° C.

[0221] NMR(CDCl₃) δ: 2.65(3H, s), 3.8-4.0(16H, m), 7.2-7.4(2H, m),7.6-7.7(1H, m), 8.2-8.3(1H, m), 12.15(1H, s)

[0222] MS m/z: 424(M⁺)

[0223] In accordance with the procedure of the Example 6, the followingcompounds were prepared from the corresponding starting materials.2-(2-acetylaminobenzimidazol-1-yl)-4-(trans-2,3-dimethylmorpholino)-6-morpholinopyrimidine(Compound 23)

[0224] Melting point: 150-153° C.

[0225] NMR(CDCl₃) δ: 1.22(3H, d, J=7 Hz), 1.25(3H, d, J=7 Hz),2.67(3H,m), 3.2-3.4(1H, m), 3.6-4.3(13H, m), 5.43(1H, s), 7.1-7.3(2H,m), 7.6-7.7(1H, m), 8.2-8.3(1H, m), 12.12(1H, s)

[0226] MS m/z: 451(M⁺)2-(2-formylaminobenzimidazol-1-yl)-4,6-dimorpholino-1,3,5-triazine(Compound 24)

[0227] Melting point: 221-223° C.

[0228] NMR(CDCl₃) δ: 3.7-4.0(16H, m), 7.2-7.4(2H, m), 7.5-7.6(1H, m),8.2-8.3(1H, m), 9.46(1H, d, J=10 Hz), 10.75(1H, d, J=10 Hz)

[0229] MS m/z: 410(M⁺)

[0230]2-(2-propionylaminobenzimidazol-1-yl)-4-(trans-2,3-dimethylmorpholino)-6-morpholino-1,3,5-triazine(Compound 25)

[0231] Melting point: 166-168° C.

[0232] NMR(CDCl₃) δ: 1.26(3H, t, J=7 Hz), 1.35(3H, d, J=6 Hz), 1.42(3H,d, J=6 Hz), 3.06(2H, q, J=7 Hz), 3.3-3.5(1H, m), 3.7-4.0(11H, m),4.3-4.5(2H, m), 7.2-7.3(2H, m), 7.6-7.7(1H, m), 8.2-8.3(1H, m),12.20(1H, s)

[0233] MS m/z: 466(M⁺)

[0234]2-(trans-2,3-dimethylmorpholino)-4-(2-formylamino-benzimidazol-1-yl)-6-morpholino-1,3,5-triazine(Compound 26)

[0235] Melting point: 189-191° C.

[0236] NMR(CDCl₃) δ: 1.35(3H, d, J=6.6 Hz), 1.42(3H, d, J=6.6 Hz),3.4-3.5(1H, m), 3.7-4.0(11H, m), 4.3-4.5(2H, m), 7.2-7.3(2H, m),7.6-7.7(1H, m), 8.2-8.3(1H, m), 9.46(1H, d, J=10 Hz), 11.78(1H, d, J=10Hz)

[0237] MS m/z: 438(M⁺)

[0238]4-(trans-2,3-dimethylmorpholino)-2-(2-formylamino-benzimidazol-1-yl)-6-morpholinopyrimidine(Compound 27)

[0239] Melting point: 143-146° C.

[0240] NMR(CDCl₃) δ: 1.39(3H, d, J=7 Hz), 1.41(3H, d, J=7 Hz),3.3-3.5(1H, m), 3.6-3.7(4H, m), 3.8-4.2(9H, m), 5.44(1H, s), 7.2-7.4(2H,m), 7.59(1H, d, J=9 Hz), 8.26(1H, d, J=9 Hz), 9.48(1H, d, J=10 Hz),11.77(1H, d, J=10 Hz)

[0241] MS m/z: 437(M⁺)

[0242]2-(cis-2,6-dimethylmorpholino)-4-(2-formylamino-benzimidazol-1-yl)-6-morpholino-1,3,5-triazine(Compound 28)

[0243] Melting point: 242-244° C.

[0244] NMR(CDCl₃) δ: 1.2-1.4(6H, m), 2.6-2.9(2H, m), 3.6-4.0(10H, m),4.3-4.6(2H, m), 7.2-7.4(2H, m), 7.58(1H, d, J=7 Hz), 8.30(1H, d, J=7Hz), 9.46(1H, d, J=10 Hz), 11.81(1H, d, J=10 Hz)

[0245] MS m/z: 438(M⁺)

EXAMPLE 7

[0246]2-(2-methoxycarbonylaminobenzimidazol-1-yl)-4,6-dimorpholino-1,3,5-triazine(Compound 29) 0.19 g (0.50 mmol) of2-(2-aminobenzimidazol-1-yl)-4,6-dimorpholino-1,3,5-triazine synthesizedin (1) of the Example 6 and 60% sodium hydride (24 mg, 0.60 mmol) addedto DMF (2 ml) were reacted at room temperature for 1 hour. The reactionmixture was added and reacted with 0.040 ml (0.55 mmol) ofchloromethylformate at room temperature for 16 hours. The reactionsolution was poured into water and extracted with methyl acetate. Theorganic layer was separated, washed with water and dried over anhydrousmagnesium sulfate. The solvent was removed under reduced pressure andthe residue was purified by silica gel column chromatography to obtain100 mg (yield: 46%) of the titled compound as colorless crystals.

[0247] Melting point: 206-209° C.

[0248] NMR(CDCl₃) δ: 3.8-3.9(19H, m), 7.2-7.4(2H, m), 7.71(1H, d, J=8Hz), 8.26(1H, d, J=9 Hz), 12.19(1H, brs)

[0249] MS m/z: 440(M⁺)

EXAMPLE 82-(6-amino-2-difluoromethylbenzimidazol-1-yl)-4-(2,2-dimethylmorpholino)-6-morpholino-1,3,5-triazine(Compound 32)

[0250] (1) 49.4 g (210 mmol) of2,4-dichloro-6-morpholino-1,3,5-triazine, 44.8 g (210 mmol) of2-difluoromethyl-5-nitrobenzimidazole and 34.5 g of potassium carbonatewere added to acetone (700 ml) and stirred at room temperature for 16hours. The reaction solution was poured into water and the resultantprecipitate was washed with water and acetone to obtain 61.4 g (yield:71%) of a mixture of4-chloro-2-(2-difluoromethyl-5-nitrobenzimidazol-1-yl)-6-morpholino-1,3,5-triazinewith4-chloro-2-(2-difluoromethyl-6-nitrobenzimidazol-1-yl)-6-morpholino-1,3,5-triazine.

[0251] (2) 0.72 g of the obtained mixture, 0.32 g (2.1 mmol) of2,2-dimethylmorpholine hydrochloride and 0.6 g of potassium carbonatewere added to DMF (10 ml) and stirred at room temperature for 16 hours.The reaction solution was poured into the water and extracted with ethylacetate. The organic layer was separated, washed with water and driedover anhydrous magnesium sulfate to obtain 0.76 g (yield: 89%) of amixture of2-(2-difluoromethyl-5-nitrobenzimidazol-1-yl)-4-(2,2-dimethylmorpholino)-6-morpholino-1,3,5-triazinewith2-(2-difluoromethyl-6-nitrobenzimidazol-1-yl)-4-(2,2-dimethylmorpholino)-6-morpholino-1,3,5-triazine.

[0252] (3) 0.76 g of the mixture obtained in (2) above was suspended inethanol (50 ml) and catalytically reduced in the presence of 0.10 g of10% Pd—C as catalyst at room temperature in hydrogen atmosphere.Insoluble was filtered out and the solvent was removed under reducedpressure and the residue was purified by silica gel columnchromatography to obtain 0.65 g (yield: 92%) of the titled compound ascolorless crystals.

[0253] Melting point: 226-227° C. (decomp.)

[0254] NMR(CDCl₃) δ: 1.28(6H, s), 3.6-3.8(16H, m), 6.7-6.8 (1H, m),7.2-7.7 (3H, m)

[0255] MS m/z: 460(M⁺)

[0256] In accordance with the procedure of the Example 8, the followingcompounds were prepared from the corresponding starting materials.

[0257]2-(6-amino-2-difluoromethylbenzimidazol-1-yl)-4-(2,3-cis-dimethylmorpholino)-6-morpholino-1,3,5-triazine(Compound 33)

[0258] Melting point: 220-222° C. (decomp.)

[0259] NMR(CDCl₃) δ: 1.22 (3H, d, J=9 Hz), 1.26 (3H, d, J=9 Hz),3.1-3.4(1H, m), 3.5-4.1 (11H, m), 4.3-4.5(1H, m), 4.5-4.7(1H, m),6.77(1H, dd, J=2 Hz, 9 Hz), 7.49(1H, t, J=54 Hz), 7.62(1H, d, J=9 Hz),7.64(1H, d, J=2 Hz)

[0260] MS m/z: 460(M⁺)

[0261]2-(4-amino-2-difluoromethylbenzimidazol-1-yl)-4,6-dimorpholino-1,3,5-triazine(Compound 34)

[0262] Melting point: 214-216° C. (decomp.)

[0263] NMR(CDCl₃) δ: 3.7-3.9(16H, m), 4.48(2H, brs), 6.63(1H, d, J=8Hz), 7.21(1H, t, J=8 Hz), 7.55(1H, t, J=54 Hz), 7.64(1H, d, J=8 Hz)

[0264] MS m/z: 432(M⁺)

EXAMPLE 9

[0265]2-(6-amino-2-difluoromethylbenzimidazol-1-yl)-4,6-dimorpholinopyrimidine(Compound 35)

[0266] In accordance with the procedure of the Example 1 except that2-difluoromethylbenzimidazole in (1) of the Example 1 was replaced by2-difluoro-6-nitrobenzimidazole, a mixture of2-(2-difluoromethyl-5-nitrobenzimidazol-1-yl)-4,6-dimorpholinopyrimidinewith2-(2-difluoromethyl-6-nitrobenzimidazol-1-yl)-4,6-dimorpholinopyrimidinewas obtained. In accordance with the procedure of (3) of the Example 8,using 0.92 g (2.0 mmol) of this mixture, 0.76 g (yield: 88%) of thetitled compound was obtained as colorless crystals.

[0267] Melting point: 218-219° C. (decomp.)

[0268] NMR(CDCl₃) δ: 3.6-3.9(18H, m), 5.49(1H, s), 6.76(1H, dd, J=2 Hz,9 Hz), 7.43(1H, t, J=54 Hz), 7.51(1H, d, J=2 Hz), 7.64(1H, d, J=9 Hz)

[0269] MS m/z: 431(M⁺)

[0270] In accordance with the procedure of the Example 9, the followingcompound was prepared from the corresponding starting material.

[0271]2-(6-amino-2-difluoromethylbenzimidazol-1-yl)-4-(2,3-cis-dimethylmorpholino)-6-morpholinopyrimidine(Compound 36)

[0272] Melting point: 155-158° C. (decomp.)

[0273] NMR(CDCl₃) δ: 1.21(3H, d, J=7 Hz), 1.22(3H, d, J=7 Hz),3.1-3.4(1H, m), 3.6-4.1(11H, m), 5.45(1H, s), 6.78(1H, dd, J=2 Hz, 9Hz), 7.44(1H, t, J=54 Hz), 7.52(1H, d, J=2 Hz), 7.65(1H, d, J=9 Hz)

[0274] MS m/z: 459(M⁺)

EXAMPLE 10

[0275]2-(2-difluoromethyl-5-hydroxybenzimidazol-1-yl)-4-(2,3-cis-dimethylmorpholino)-6-morpholino-1,3,5-triazine(Compound 37)

[0276] In accordance with the procedure of the Example 4 except that2-difluoromethylbenzimidazole in (1) of the Example 4 was replaced by2-difluoromethyl-5-tert-butyldimethyl-silyloxybenzimidazole, obtainedwas2-(2-difluoromethyl-5-tert-butyldimethylsilyloxybenzimidazol-1-yl)-4-(2,3-cis-dimethylmorpholino)-6-morpholino-1,3,5-triazine.120 mg (0.22 mmol) of the obtained compound dissolved in THF (2 ml) wasadded with a solution of tetrabutylammoniumfluoride (1 M) in THF (0.5ml) and stirred at room temperature for 30 minutes. The reactionsolution was poured into water and extracted with ethyl acetate. Theseparated organic layer was washed with water and dried over anhydrousmagnesium sulfate. The solvent was removed under reduced pressure andthe residue was purified by silica gel column chromatography to obtain75 mg (yield: 79%) of the titled compound as colorless crystals.

[0277] Melting point: 170-175° C. (decomp

[0278] NMR(CDCl₃) δ: 1.1-1.3(6H, m), 3.1-3.4(1H, m), 3.5-4.1(11H, m),4.3-4.7 (2H, m), 7.04 (1H, d, J=9 Hz), 7.29(1H, d, J=3 Hz) 7.54(1H, dt,J=4 Hz, 54 Hz), 8.18(1H, dd, J=3 Hz, 9 Hz)

[0279] MS m/z: 461(M⁺)

[0280] In accordance with the procedure of the Example 10, the followingcompounds were prepared from the corresponding starting materials.

[0281]2-(2-difluoromethyl-4-hydroxybenzimidazol-1-yl)-4-(2,2-dimethylmorpholino)-6-morpholino-1,3,5-triazine(Compound 38)

[0282] Melting point: 228-231° C. (decomp.)

[0283] NMR(CDCl₃) δ: 1.28(6H, s), 3.6-3.9(14H, m), 6.8-6.9(2H, m),7.2-7.9(3H, m)

[0284] MS m/z: 461(M⁺)

[0285]2-(2-difluoromethyl-5-hydroxybenzimidazol-1-yl)-4-(2,2-dimethyloxazolidin-3-yl)-6-morpholino-1,3,5-triazine(Compound 39)

[0286] Melting point: 239-243° C. (decomp.)

[0287] NMR(CDCl₃) δ: 1.59(6H, s), 3.8-4.0(10H, m), 5.25(2H, s), 7.03(1H,d, J=9 Hz), 7.29(1H, s), 7.56(1H, t, J=54 Hz), 8.20(1H, d, J=9 Hz)

[0288] MS m/z: 447(M⁺)

EXAMPLE 11

[0289]2-(2-difluoromethyl-5-hydroxybenzimidazol-1-yl)-4,6-dimorpholinopyrimidine(Compound 40)

[0290] In accordance with the procedure of the Example 1 except that2-difluoromethylbenzimidazole in (1) of the Example 1 was replaced by2-difluoromethyl-5-tert-butyldimethylsilyloxybenzimidazole, obtained was2-(2-difluoromethyl-5-tert-butyldimethylsilyloxybenzimidazol-1-yl)-4,6-dimorpholinopyrimidine.0.55 g (1.0 mmol) of the obtained compound dissolved in THF (10 ml) wasadded with a solution of tetrabutylammoniumfluoride (1 M) in THF (2 ml)and stirred at room temperature for 30 minutes. The reaction solutionwas poured into water and extracted with ethyl acetate. The separatedorganic layer was washed with water and dried over anhydrous magnesiumsulfate. The solvent was removed under reduced pressure and the residuewas purified by silica gel column chromatography to obtain 0.40 g(yield: 93%) of the titled compound as colorless crystals.

[0291] Melting point: 223-226° C. (decomp.)

[0292] NMR(CDCl₃) δ: 3.5-4.0(16H, m), 5.50(1H, s), 7.00(1H, dd, J=2 Hz,9 Hz), 7.29(1H, d, J=9 Hz), 7.49(1H, t, J=53 Hz), 8.01(1H, d, J=9 Hz)

[0293] MS m/z: 432(M⁺)

EXAMPLE 12

[0294]2-(2-aminobenzimidazol-1-yl)-4-(cis-2,3-dimethyl-morpholino)-6-morpholinopyrimidinehydrochloride (Compound 30)

[0295] 1.23 g (3.0 mmol) of2-(2-aminobenzimidazol-1-yl)-4-(cis-2,3-dimethylmorpholino)-6-morpholinopyrimidineobtained in the Example 2 and dissolved in 2N hydrochloric acid (3.0 ml)was condensed under reduced pressure and the resultant crystals werefiltered out to obtain 1.20 g (yield: 90%) of the titled compound ascolorless crystals.

[0296] Melting point: 151-155° C.

[0297] NMR(D₂O) δ: 1.07(3H, d, J=6 Hz), 1.22(3H, d, J=6 Hz),3.0-4.1(14H, m), 5.51(1H, s), 7.0-7.3(3H, m), 7.7-7.9(1H, m)

[0298] MS m/z: 410[M+1]⁺

[0299] In accordance with the procedure of the Example 12, the followingcompound was obtained from the corresponding starting material.

[0300]2-(2-aminobenzimidazol-1-yl)-4-(trans-2,3-dimethyl-morpholino)-6-morpholinopyrimidinehydrochloride (Compound 31)

[0301] Melting point: 141-145° C.

[0302] NMR(D₂O) δ: 1.30(3H, d, J=7 Hz), 1.38(3H, d, J=7 Hz), 3.2-3.5(5H,m), 3.6-4.1(9H, m), 5.58(1H, s), 7.07(1H, t, J=8 Hz), 7.19(1H, d, J=8Hz), 7.28(1H, t, J=8 Hz), 7.74(1H, d, J=8 Hz)

[0303] MS m/z: 410[M+1]⁺

CAPABILITY OF EXPLOITATION IN INDUSTRY

[0304] The compounds of the present invention exhibit apparently by farstrong antitumor activities with no aromatase inhibitory activities incomparison with conventional s-triazine and pyrimidine derivatives andcan be applied to treatment on solid cancers.

What is claimed is:
 1. A heterocyclic compound represented by theformula I or a pharmaceutically acceptable salt thereof:

wherein X represents nitrogen atom or CH; R₁ represents CH_(n)F_(3-n)(wherein n is 1 or 2), hydroxy C₁-C₆ alkyl, NHR₆ [wherein R₆ representshydrogen atom or COR (wherein R represents hydrogen atom, C₁-C₆ alkyl orC₁-C₆ alkoxy)]; R₂ represents morpholino (which may be substituted withone to four C₁-C₆ alkyl), thiomorpholino, piperidino, pyrrolidinyl(which may be substituted with hydroxy C₁-C₆ alkyl), oxazolidinyl (whichmay be substituted with one or two C₁-C₆ alkyl) ortetrahydro-1,4-thiazin-1-oxo-4-yl; R₃ and R₄ each represent hydrogenatom or C₁-C₆ alkyl; and R₅ represents hydrogen atom, amino or hydroxyl.2. The compound according to claim 1 wherein R₁ is difluoromethyl. 3.The compound according to claim 1 wherein R₁ is difluoromethyl, R₂ ismorpholino which may be substituted with one to three methyl and R₃ andR₄ each are hydrogen atom or methyl.
 4. The compound according to claim1 wherein R₁ is difluoromethyl, R₂ is morpholino which may besubstituted with one to three methyl, R₃ and R₄ each are hydrogen atomand R₅ is amino or hydroxyl.
 5. The compound according to claim 1wherein R₁ is hydroxymethyl.
 6. The compound according to claim 1wherein R₁ is hydroxymethyl, R₂ is morpholino which may be substitutedwith one or two methyl and R₃ and R₄ each are hydrogen atom or methyl.7. The compound according to claim 1 wherein R₁ is amino, formylamino oracetylamino.
 8. The compound according to claim 1 wherein R₁ is amino,formylamino or acetylamino, R₂ is morpholino which may be substitutedwith one or two methyl, and R₃ and R₄ each are hydrogen atom.
 9. Anantitumor agent comprising at least one of compounds as claimed in anyof claims 1 to 8 as effective component.
 10. A pharmaceuticalcomposition including the compound as claimed in any of claims 1 to 8together with pharmaceutically acceptable diluent or carrier.